We recently demonstrated that successful resolution of acute hepatitis C in chimpanzees primes a protective memory T cell response. Depletion of memory CD8+ T cells with subset-specific antibodies immediately before re-infection resulted in prolonged viremia. Infections never resolved if CD4+ T cells were depleted. Indeed, without helper activity memory CD8+ T cells selected for escape mutations in MHC class I restricted epitopes of the virus. These results indicate an essential role for both T cell subsets in control of HCV replication but why they usually fail is not known. T cell responses appear to focus on a limited set of MHC class I and II epitopes at the point infection resolves and later broaden to include sub-dominant epitopes. Thus, while the response appears multi-specific, it effectively targets a limited set of dominant epitopes when virus replication (and errors by the RNA polymerase) are at a peak. Specific aim 1 is to determine if this causes mutational escape of dominant MHC class II epitopes. Mutational escape will be compared with other potential mechanisms of CD4+ T cell silencing including failure to expand, acquire function, or follow a normal differentiation program after antigen activation. MHC class II tetramer technology adapted to chimpanzees will facilitate the analysis. Specific aim 2 is to identify defects in CD8+ T cells during acute hepatitis C and to determine if they occur coincident with CD4+ T cell loss. Finally, specific aim 3 will test the limits of T cell protection against persistence by rechallenging immune animals with virus variants that contain adaptive mutations in dominant MHC class I and II epitopes. Our three specific aims are to: Specific Aim 1. Compare how mutational escape in MHC class II epitopes versus functional defects in CD4+ T cells contribute to persistence of HCV. Specific Aim 2. Determine how HCV-specific CD8+ T cells are inactivated during acute hepatitis C and whether these defects are precipitated by the sudden loss of CD4+ T cell help that is characteristic of infections that persist. Specific Aim 3. Determine if transmission of HCV variants containing escape mutations in dominant MHC class I or II epitopes can subvert protective memory T cell responses in immune chimpanzees.